Alcohol use disorders are an enormous public health problem. Recent advances in understanding the effects of alcohol on the brain and behavior present an opportunity to advance medication development. Neurotransmission at NMDA receptors may contribute to many of alcohol's effects and it is postulated that modulation of NMDA neurotransmission may be effective in the treatment of alcohol use disorders. In fact, the NMDA modulator acamprosate is effective in the treatment of alcohol dependence. We propose to develop and implement human laboratory and clinical models to screen promising medications and establish whether modulation of the NMDA receptor system with memantine, a non-competitive NMDA antagonist, has beneficial effects in the treatment of alcohol dependence. For comparison we will test acamprosate, a polyamine site NMDA modulator with proven efficacy in the treatment of alcohol dependence. Residential laboratory studies will include paradigms designed to model multiple aspects of alcoholism using non-treatment seeking moderate to heavy social drinkers. In Studies 1 and 2 we will compare the interaction of acute pretreatment with acamprosate or memantine on the effects of alcohol intoxication. In Studies 3 and 4 we will evaluate the effects of maintenance on acamprosate or memantine on reactivity to alcohol cues, and we will also evaluate the effects of maintenance on acamprosate or memantine on alcohol choice and self-administration. In Study 5 we will evaluate the effects of acamprosate and memantine, given acutely and repeatedly, on the discriminative stimulus effects of alcohol. In Study 6, we are proposing a strategy for improving initial pilot screening of medications that involves testing acamprosate, memantine and placebo in a relatively small N. placebo-controlled trial in alcohol-dependent individuals. Inclusion of this clinical trial model is important for predicting the validity of the laboratory models we are proposing. The experimental verification that acamprosate and memantine modulate alcohol intoxication, self-administration, cue-reactivity, discriminative effects, and preliminary clinical efficacy, could have major implications for the treatment of alcohol use disorders. This application represents, to our knowledge, the first attempt to systematically evaluate the contribution of NMDA receptor-mediated neurotransmission on alcohol's action in humans from the perspective of medication development.